Goals and Analytical Methodologies for Protein Disposition Studies

Ferraiolo, Bobbe L.; Mohler, Marjorie A.

doi:10.1007/978-1-4899-2329-5_1

Cited by 15 publications

(14 citation statements)

References 140 publications

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“…Nonspecific degradation processes by circulating proteases or hepatic catabolism are further potential mechanisms for the clearance of rhLIF (Ferraiolo et al, 1992). These nonspecific, high-capacity elimination processes are included in the proposed model as a single first-order elimination process from the central compartment (k e ).…”

Section: Methodsmentioning

confidence: 99%

“…Protein clearance by receptormediated endocytosis has been demonstrated for a number of proteins that exhibit nonlinear plasma kinetics, including erythropoietin (Chapel et al, 2001), granulocyte colony stimulating factor (Terashi et al, 1999), and hepatocyte growth factor (Liu et al, 1995). Additional mechanisms such as nonspecific renal and hepatic elimination processes and proteolytic degradation may also contribute to the removal of cytokines from the systemic circulation (Ferraiolo et al, 1992).…”

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confidence: 99%

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Pharmacokinetics of Recombinant Human Leukemia Inhibitory Factor in Sheep

Segrave

Mager

Charman

et al. 2004

J Pharmacol Exp Ther

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The pharmacokinetics of recombinant human leukemia inhibitory factor (rhLIF) were investigated following i.v. and s.c. administration of a wide range of dose levels. Parallel studies were conducted where single i.v. bolus doses of 12.5, 25, 100, 250, 500, or 750 g/kg rhLIF (n ϭ 2) or s.c. doses of 10, 20, or 50 g/kg rhLIF (n ϭ 4) were administered to sheep. Blood samples were collected for up to 24 h postdosing, and the plasma concentrations of rhLIF were analyzed by enzyme-linked immunosorbent assay. Noncompartmental analysis demonstrated an increase in the terminal elimination half-life (from 0.27 to 2.29 h) and a decrease in systemic clearance (from 5.18 to 1.09 ml/min/kg) with increasing i.v. doses of rhLIF, suggesting nonlinear pharmacokinetic behavior. A greater than proportional increase in the area under the plasma concentration-time curve with dose also indicated significantly nonlinear pharmacokinetics after s.c. administration. A mechanistic compartmental model was developed to characterize the pharmacokinetics of rhLIF. The key feature of the model accounting for the nonlinear pharmacokinetic behavior of rhLIF was high-affinity, saturable receptor binding and subsequent cellular internalization and degradation. The apparent total density of LIF cell surface receptors and receptor turnover dynamics were included in the model, along with nonspecific binding and linear elimination from the systemic circulation. The absorption of rhLIF from the s.c. injection site into the systemic circulation was characterized by a first-order absorption process via a delay compartment. The proposed model satisfactorily captured the complex pharmacokinetic profiles of rhLIF following both i.v. and s.c. administration.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

Pharmacokinetics of Recombinant Human Leukemia Inhibitory Factor in Sheep

Segrave

Mager

Charman

et al. 2004

J Pharmacol Exp Ther

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“…Enfuvirtide is primarily used in salvage therapy as part of drug combination regimens. Because enfuvirtide is a peptide, it is expected to undergo catabolism rather than metabolism by cytochrome P450 enzymes (Ferraiolo, Mohler, Gloff, 1992). Enfuvirtide did not inhibit the activities of CYP1A2, CYP2C19, CYP2D6, CYP2E1 or CYP3A4 in an open label, crossover trial in 12 HIV-infected adults (Hammer et al, 2006).…”

Section: Fusion Inhibitors (Fis)mentioning

confidence: 99%

Twenty-six years of HIV science: an overview of anti-HIV drugs metabolism

Andrade

Freitas

Oliveira

2011

Braz. J. Pharm. Sci.

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From the identification of HIV as the agent causing AIDS, to the development of effective antiretroviral drugs, the scientific achievements in HIV research over the past twenty-six years have been formidable. Currently, there are twenty-five anti-HIV compounds which have been formally approved for clinical use in the treatment of AIDS. These compounds fall into six categories: nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), cell entry inhibitors or fusion inhibitors (FIs), co-receptor inhibitors (CRIs), and integrase inhibitors (INIs). Metabolism by the host organism is one of the most important determinants of the pharmacokinetic profile of a drug. Formation of active or toxic metabolites will also have an impact on the pharmacological and toxicological outcomes. Therefore, it is widely recognized that metabolism studies of a new chemical entity need to be addressed early in the drug discovery process. This paper describes an overview of the metabolism of currently available anti-HIV drugs.Uniterms: AIDS/treatment. Drugs/anti-HIV. Drugs/metabolism. Antiretroviral drugs. Biotransformation.Da identificação do HIV como o agente causador da AIDS, ao desenvolvimento de fármacos antirretrovirais eficazes, os avanços científicos na pesquisa sobre o HIV nos últimos vinte e seis anos foram marcantes. Atualmente, existem vinte e cinco fármacos anti-HIV formalmente aprovados pelo FDA para utilização clínica no tratamento da AIDS. Estes compostos são divididos em seis classes: inibidores nucleosídeos de transcriptase reversa (INTR), inibidores nucleotídeos de transcriptase reversa (INtTR), inibidores não-nucleosídeos de transcriptase reversa (INNTR), inibidores de protease (IP), inibidores da entrada celular ou inibidores de fusão (IF), inibidores de co-receptores (ICR) e inibidores de integrase (INI). O metabolismo consiste em um dos maiores determinantes do perfil farmacocinético de um fármaco. A formação de metabólitos ativos ou tóxicos terá impacto nas respostas farmacológicas ou toxicológicas do fármaco. Portanto, é amplamente reconhecido que estudos do metabolismo de uma nova entidade química devem ser realizados durante as fases iniciais do processo de desenvolvimento de fármacos. Este artigo descreve uma abordagem do metabolismo dos fármacos anti-HIV atualmente disponíveis na terapêutica.Unitermos: AIDS/tratamento. Fármacos/anti-HIV. Fármacos/antirretrovirais. Fármacos/metabolismo. Biotransformação. INTRODUCTIONThe human immunodeficiency virus (HIV) has been established as the causative agent of the acquired immunodeficiency syndrome (AIDS) for over twentysix years now (Barré-Sinoussi et al., 1983). During this time, an unprecedented success has been achieved in discovering anti-HIV drugs as reflected by the fact that there are now more drugs approved for the treatment of HIV than for all other viral infections put together (Mehellou, De Clercq, 2009). Despite this progress...

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“…It is imperative to establish whether the radioactive species in a given biological sample represent free or bound intact labeled drug, radiolabeled degradation products, or liberated label (FERRAIOLO and MOHLER 1992). Administration of radioiodinated recombinant human growth hormone in clinical studies has shown that free iodine appears in plasma within minutes postdose, presumably through deiodination by ubiquitous deiodinase enzymes.…”

Section: Radiolabel Realitiesmentioning

confidence: 99%

“…For example, preclinical and clinical studies with recombinant human interferony have yielded absolute subcutaneous bioavailabilities as determined by ELISA of greater than 100% (CHEN et al 1990;FERRAIOLO et al 1988aFERRAIOLO et al , 1990bKURZROCK et al 1985;REED et al 1990). It has been suggested that slightly degraded forms of exogenous interferon-y may circulate after intravenous and subcutaneous administration and that the production of these metabolites may be route dependent (FERRAIOLO et al 1990b;FERRAIOLO and MOHLER 1992). These degraded forms may have different disposition properties than the parent protein and may cross-react in the parent immunoassay; this could significantly interfere with the determination of bioavailability.…”

Section: B) Metabolitesmentioning

confidence: 99%